Pregnatetraenes

ABSTRACT

NEW PREGNATETRAENES WHICH POSSESS OESTROGENIS AND HYPOCHOLESTEROLEMIC ACTIVITIES HAVE THE FOLLOWING FORMULA:   3-(R1-O-),14,17-(-O-CH(-CH3)-O-),20-(R2-N=)PREGNA-1,2,4,   9-TETRAENE   WHEREIN R1 REPRESENTS A HYDROGEN ATOM, A LOWER ALKYL GROUP HAVING LESS THAN 6 CARBON ATOMS AND WHICH MAY BE SUBSTITUTED BY A DIMETHYLAMINO GROUP, OR AN ACYL RESIDUE DERIVED FROM AN ORGANIC CARBOXYLIC ACID OR FROM AN INORGANIC ACID; R2 REPRESENTS A GROUP OR3, WHEREIN R3 REPRESENTS A HYDROGEN ATOM, A LOWER ALKYL GROUP HAVING LESS THAN 6 CARBON ATOMS, AN ARYL GROUP, AN ARYLMETHYL GROUP OR AN ACYL RESIDUE DERIVED FROM AN ORGANIC CARBOXYLIC ACID OR FROM AN INORGANIC ACID, OR R2 REPRESENTS A GROUP   -N(-R4)-R5   WHEREIN R4 AND R5 MAY BE THE SAME OR DIFFERENT AND REPRESENT A HYDROGEN ATOM, A LOWER ALKYL GROUP HAVING LESS THAN 6 CARBON ATOMS, AND ACYL RESIDUE DERIVED FROM AN ORGANIC CARBOXYLIC ACID, THE CARBOXAMIDE GROUP OR THE GROUP -CO-CH2-N+7CH3)3C1-.

United States Patent ()1 fice.

3,766,171 PREGNATETRAENES Arthur Friedrich Marx and Hermanus JacobusKooreman, Delft, Netherlands, assignors to Koninklijke NederlandscheGist-en Spiritusfabriek, N.V., Delft, Netherlands No Drawing. Filed Mar.5, 1971, Ser. No. 121,581 Claims priority, application Great Britain,Mar. 6, 1970, 10,996/70 Int. Cl. C07c 173/00 U.S. Cl. 260-23955 D 40Claims ABSTRACT OF THE DISCLOSURE New pregnatetraenes which possessoestrogenic and hypocholesterolemic activities have the followingformula:

wherein R, and R may be the same or ditferent and represent a hydrogenatom, a lower alkyl group having less than 6 carbon atoms, an acylresidue derived from an organic carboxylic acid, the carboxamide groupor the group CO-CH -N+(CH Cl This invention relates to newtherapeutically useful pregnatetraenes, to processes for theirpreparation and to pharmaceutical compositions containing them.

The pregnatetraenes of the present invention are the newZO-iminopregnatetraene derivatives of the general formula:

wherein R represents a hydrogen atom, a lower alkyl group having lessthan 6 carbon atoms and which may be substituted by a dimethylaminogroup, or an acyl residue derived from an organic carboxylic acid orfrom an inorganic acid; R represents a group 0R wherein R represents ahydrogen atom, a lower alkyl group having less than 6 carbon atoms, anaryl group, an aryl- 3,766,171 Patented Oct. 16, 1973 methyl group or anacyl residue derived from an organic wherein R and R may be the same ordifferent and represent a hydrogen atom, a lower alkyl group having lessthan 6 carbon atoms, an acyl residue derived from an organic carboxylicacid, the carboxamide group or the group --C-OCH -N+ (CH C1-.

The pregnatetraenes of the general Formula I are therapeutically usefulcompounds possessing oestrogenic and hypocholesterolemic activities; insome cases there is a favorable ratio between both activities. Thesecompounds can be applied for human as well as veterinary F565; they canbe administered orally as well as parenteral- The 20-iminopregnatetraene derivatives of the general Formula I may be prepared bymethods known for the preparation of analogous compounds. The termsmethods known per se and in known manner" used hereafter refer tomethods heretofore used or described in chemical literature.

According to a feature of the invention, .the compounds of the generalFormula I are prepared by reacting a pregnatetraen-ZO-one of the generalformula -LHCHs (III) except the 3-hydroxy derivative which is disclosedin the specification of co-pending U.S. patent application Ser. No.856,475 in Marx et al., wherein R is as hereinbefore defined, withparaldehyde in the presence of a strong acid as catalyst, for exampleperchloric or p-toluene sulphonic acid, and in an inert organic solvent,for example dioxane or tetrahydrofuran.

The 14a,17ct dihydroxypregnatetraene derivatives of Formula III are newcompounds too; they can be prepared in known manner. For example, thepregnatetraene of Formula III, wherein R represents a hydrogen atom,i.e. 3,14a,l7u trihydroxy-19-norpregna-1,3,5(10),9(11)- tetraen-ZO-one,can be prepared in four reaction steps from14a,17a-dihydroxyprogesterone.

(a) The latter compound can be microbiologically hydroxylated in thell-position, for example with Cunninglzamella blackesleeana, CurvulariaIunata, or Aspergillus oclzraceus, to give11,14a,17u-trihydroxyprogesterone.

(b) The product of (a) can be dehydrated to the 9(11)- dehydroderivative, for example, by acylation for example with methane sulphonylchloride, to give 1la,l4ct,17oc-tlihydroxyprogesterone ll-methanesulphonate, which, in a suitable organic solvent for exampledimethylformamide, can then be heated with lithium chloride to give14a,17adihydroxy 9(11)-dehydroprogesterone. The llfl-isomer,l1,3,14a,17a-trihydroxyprogesterone, can be reacted withN-bromo-acetamide to give the corresponding 9(11)- dehydro derivative.Preferably, this reaction is carried out at room temperature, in asuitable organic medium, for example pyridine.

(c) The product of (b) can be dehydrogenated in the 1,2-position, forexample by reaction with selenium oxide or2,3-dichloro-4,5-dicyano-benzoquinone, or by fermentation with asuitable microorganism, such as Corynebacterium simplex, to givel4a,l7u-dihydroxy-l,9(1l)-bisdehydroprogesterone, that is,14a,17a-dihydroxy-pregna-1,4,9 l 1)-triene-3,20-dione.

(d) The above pregnatriene can then be aromatized, for example byheating in pyridine with zinc dust, to give 3,14ot,17a trihydroxyl9-nor-pregna-l,3,5(10),9(ll)- tetraen-ZO-one.

This compound can then be used in the above reaction with paraldehyde toprepare 3 hydroxy-14a,17a-ethylidenedioxy 19nor-pregna-1,3,5(10),9(11)-tetraen-20- one. The latter compound can thenbe used again to prepare other 14oc,17o ethylidenedioxy-pregnatetraenesof Formula II.

For example, the pregnatetraenes of Formula II, Wherein R represents alower alkyl group which may be substituted by a dimethylamino group, canbe prepared by reacting 3 hydroxy 14ot,17aethylidenedioxy-19-norpregna-1,3,5(10),9(11)-tetraen-20-one with anappropriate halide of the formula R -hal or a sulphate of the formula (RSO preferably in an organic medium, for example tetrahydrofuran orchloroform, and in the presence of an alkali metal hydroxide solution oran alkali metal alkyl solution, for example butyl lithium in nhexane.

The pregnatetraenes of Formula II, wherein R represents an acyl residuecan be prepared by reacting 3-hydroxy14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10), 9(11)-tetraen-20-onewith the appropriate acid anhydride in the presence of an acid oralkaline catalyst or by reaction with an acid halide in an organicsolvent, for example pyridine. Anhydrides and acyl halides of carboxylicacids which have up to 11 carbon atoms are most generally employedincluding cylic carboxylic acids such as adamantane carboxylic acid.

According to a modification of these processes, 3-hydroxy14a,17a-ethylidenedioxy-19-nor-pregna1,3,5(10), 9(1l)-tetraen-20-one isfirst reacted with an amine of the formula H NR to form aZO-iminopregnatetraene of Formula I, wherein R represents a hydrogenatom, and then this compound is converted into the corresponding 3-etheror 3-ester in the manner described above.

Pregnatetraenes of general Formula I prepared according to the processdescribed above can be converted into other ZO-iminQpregnatetraenes ofthe invention.

For example, a pregnatetraen-ZO-one 20-oxime of the general formula:

wherein R is as hereinbefore defined, can be converted into a20-iminopregnatetraene of the Formula I, wherein R represents a loweralkyl group having less than 6 carbon atoms, an aryl group or an arylmethyl group, by reaction with an appropriate halide of the formula R-hal or a sulphate of the formula (R SO in analogous man- 20 ner asdescribed above for the preparation of pregnatetraenes of Formula II,wherein R represents a lower alkyl group. Phenyl and benzyl groups areparticularly preferred as the aryl and aryl-methyl groups respectively.Pregnatetraenes of the general Formula I, wherein R, represents an acylresidue derived from an organic acid or from an inorganic acid, can beprepared by reacting a pregnatetraen-ZO-one 20-oxime of the Formula IVwith an appropriate acid anhydride or halide. The reaction is preferablycarried out in an organic medium, for example pyridine, at roomtemperature. The acyl group may be from almost any carboxylic acid,including hetero carboxylic acids, i.e. acetic acid, myristic acid,isonicotinic acid, thiophene carboxylic acid and the like. Mostpreferably, the acyl group contains up to 14 carbon atoms.

When in these processes the starting material is a pregnatetraen-ZO-one20-oxime of Formula IV, wherein R represents a hydrogen atom, thishydrogen atom will simultaneously be replaced too by the group R wherebythe corresponding 3-ethers or 3-esters are obtained.

wherein R is as hereinbefore defined and R represents a hydrogen atom ora lower alkyl group having less than 6 carbon atoms, can also beconverted into other 20-iminopregnatetraenes of the invention.

Pregnatetraenes of the general Formula I, wherein R represents an acylresidue derived from an organic carboxylic acid, can be prepared byreacting a pregnatetraen- 20-one 20-hydrazone of Formula V with anappropriate acid anhydride or halide in the same manner as describedabove for the preparation of other acyl derivatives. Anhydrides and acylhalides of carboxylic acids which have up to 11 carbon atoms are mostgenerally employed, includingdcyclic carboxylic acids such as adamantanecarboxylic acr In case R represents a hydrogen atom and the reaction iscarried out with a halide of an organic carboxylic acid, generallypregnatetraen-ZO-one 20-N,N-diacylhydrazones are obtained.

When a pregnatetraen-20-one 20-hydrazone of the Formula V, wherein Rrepresents a hydrogen atom, is reacted as described above, with an acidanhydride or acyl halide, the 3-hydroxy1 group is convertedsimultaneously into the corresponding 3-ester group.

The pharmaceutical compositions of the invention comprise at least one20iminopregnatetraene of general Formula I and a pharmaceuticallyacceptable carrier or diluent. The compositions may take any of theforms customarily employed for administration of therapeutically atcivesubstances, but the preferred types are those suitable for oraladministration, especially tablets, including sustained release tablets,pills and capsules, and those suitable for parenteral administration.

The tablets and pills may be formulated in the usual manner with one ormore pharmaceutically acceptable diluents or excipients, and can includelubricants. Capsules made of adsorbable material, such as gelatin, maycontain the active substance alone or in a mixture, with a solid orliquid diluent. Liquid preparations may be in the form of suspensions,emulsions, syrups or elixirs of the active substance in water or otherliquid media commonly used for making orally acceptable pharmaceuticalformulations.

The active substance may also be made up in a form suitable forparenteral administration, i.e. as a suspension or emulsion in sterilewater or an organic liquid usually employed for injectable preparations,for example a vegetable oil such as corn or olive oil, or a sterilesolution in water or an organic solvent.

For parenteral administration, the daily dosage may be 100 to 250 mg.; asuitable concentration of the active compound in an injectablepreparation is 100 mg./ml. For oral administration, the daily dosage maybe 0.1- 50 mg.

A suitable pharmaceutical composition of the invention can be preparedby dissolving 8 g. of 3-methoxy-14' ,17'yethylidenedioxy pregna 1,3,510),9(l1)-tetraen-20-one ZO-N-methylhydrazone in 1 l. of purified cornoil and filtering the solution obtained. Soft gelatine capsules are thenfilled each with 0.25 ml. of this solution.

The following examples illustrate the preparation of the newpregnatetraenes of the present invention.

EXAMPLE I (a) 5.5 l. of nutrient medium consisting of 0.5% of glucoseand 0.5% of corn steep liquor were inoculated with 275 ml. of shakeculture of Aspergillus ochraceus. The microorganism was grown at 26 C.with vigorous stirring and aeration. After 24 hours a solution of 1.4 g.of 14a,17a-dihydroxyprogesterone in ml. of dimethylformamide was added.After 72 hours, the conversion being complete, the culture broth wasfiltered and the filtrate extracted three times with 1 l. of methylisobutyl ketone. The extract was concentrated under reduced pressure andthe residue crystallized from methanol; yield: 0.4 g. of11u,14a,17m-trihydroxyprogesterone.

Melting point: 232-2345 C.

I.R. (in CHCl v =3608, 3485, 1711, 1665, 1612 and 1350 cm.

(b) To a stirred suspension of 5 g. of 11a,14a,17a-tl1-hydroxyprogesterone in 50 ml. of pyridine, 1.2 ml. of methanesulphonylchloride was added dropwise. The reaction mixture was kept atroom temperature for 90 minutes and then poured into 750 ml. of water,thereby obtaining 5.6 g. of 11a,l4a,17a-trihydroxyprogesteronell-methane sulphonate.

Melting point: 160-161 C.

LR. (in CHCl u =3600, 3505, 1709, 1665, 1610, 1350, 1333, 1170, 921 and900 cmr (c) A solution of 5.5 g. of 11a,14a,17a-trihydroxyprogesteronell-methane sulphonate and 5.5 g. of lithium chloride in 55 ml. ofdimethylformamide was kept at 100 C. for 30 minutes. To the cooledreaction mixture 20 ml. of water were added, yielding 3.5 g. of14a,17adihydroxy-9 1 1 )-dehydroprogesterone.

Melting point: 235-241 C.

N.M.R. (in CDCl +some DMSO-d 6:0.58, 1.34, 2.15, about 4.0, 5.58 and5.68 p.p.m.

Molecular ion peak in mass spectrum:

Calculated for C I-1 0 344; found: 344.

(d) A mixture of 10 g. of 14a,l7u-dihydroxy-9(11)- dehydroprogesterone,6.6 g. of selenium oxide, 2 ml. of pyridine and 500 ml. of tert. butanolwas refluxed for 17 hours. The precipitated selenium was filtered off,the filtrate diluted with 2.5 l. of methyl isobutyl ketone and washedwith N sodium hydroxide solution, 0.5 N sulfuric acid and water. Theorganic fraction was concentrated and the brown, crystalline residuetriturated with 50 ml. of methanol yielding 2.0 g. of nearly white14a,17a-dihydroxy- 1,9 1 1 )-bisdehydroprogesterone.

Melting point: 268-272 C.

I.R. (in CHCl v =3605, 3560, 3475, 1710, 1662, 1622, 1603 and 1350 cm.

(e) A mixture of 1.0 g. of 14u,17a-dihydroxy-1,9(11)-bisdehydroprogesterone, 30 ml. of pyridine containing 0.5 ml. of water,and 20 g. of zinc dust was heated under reflux with stirring for 210min. After cooling, the zinc was removed by filtration and washed withmethyl isobutyl ketone. The filtrate was concentrated and the residuedissolved in 25 ml. of methyl isobutyl ketone and this solution waswashed with N sulfuric acid and water. The solvent was evaporated invacuo and the residue was crystallized from methanol; yield 0.50 g. of3,140t,17mtrihydroxy 19 nor-pregna-l,3,5(10),9(11)-tetraen-20- one.

Melting point: 230-235 C.

N.M.R. (in a mixture of CD01 and DMSO-d 6:0.68, 2.23, 6.23 (broad),6.55, 6.6 and 7.5 (AB- spectrum) p.p.m.

(f) 2.5 g. of 3,14a,Not-trihydroxy-19-nor-pregna-1,3,5-(10),9(11)-tetraen20-one were stirred during 10 minutes at roomtemperature with 15 ml. of dioxane, 15 ml. of paraldehyde and 0.13 ml.of a 70% perchloric acid solution in water. The reaction mixture wasdiluted with methyl isobutyl ketone and the solution was washed with asodium bicarbonate solution and with water. Yield: 600 mg. of3-hydroxy-14a,17a-ethylidenedioxy-19-norpregna-1,3,5 10) ,9 1 1)-tetraen-20-one.

Melting point: 198-202 C.

N.M.R. (in CDCl;,): 6:0.78, 1.34 (dublet), 2.22, 5.21 (quadruplet),6.19, 6.60, 6.7-7.5 (AB-spectrum) p.p.m.

(g) 17.5 g. of 3-hydroxy-14a,17u-ethylidenedioxy-19- nor-pregna-1,3,5(10),9 (1 l -tetraen-20-one were stirred in a mixture of 350 ml. ofchloroform and 350 ml. of a 30% potassium hydroxide solution in water.70 ml. of dimethyl sulphate were added dropwise and the mixture wasstirred for another 15 minutes at room temperature. The organic layerwas separated and washed with water until neutral and then concentratedby evaporation of the solvent. The solid residue was crystallised frommethanol.

Yield: 12.9 g. of 3-methoxy-14a,17a-ethylidenedioxy- 19-nor-pregna-1,3,510 ,9 11)-tetraen-20-one.

Melting point: 153-157 C.

IR. (in CHCl u =2843, 1710, 1630, 1608, 1565, 1492, 1360 and 1140 cm.-

(h) To a stirred solution of 37.5 g. of hydroxyl amine hydrochloride inml. of water were subsequently added 150 ml. of a 10% solution of sodiumhydroxide in water, 15 g. of 3-methoxy-14u,l7a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one and 1 l. of ethanol. Themixture was boiled and then water was added until dissolving wascompleted. After heating under reflux for 10 minutes the hot reactionmixture was filtrated and the filtrate was cooled in a refrigerator.

Yield: 12.7 g. of 3-methoxy-14a,17a-ethyliedendioxy- 19-nor-pregna-1,3,510) ,9 1 1 -tetraen-20-one 20-oxime.

Melting point: -1925 C.

A (in CH OH): 263, 299 and 308 nm.; E}? =454, 79 and 60.

LR. (in CHCl v =about 3590, 2842, 1630, 1607, 1565, 1490 and 1112 emf- 7N.M.R. (in CDCl 6:0.79, 1.31 (doublet), 1.97, 3.79, 5.25 (quadruplet),6.27, 6.63, 6.7 and 7.6 (AB- spectrum) p.p.m.

Molecular ion peak in mass spectrum: Calculated for C H NO 383; found:383.

EXAMPLE II In an analogous way to the procedure described in Example I,3 hydroxy 140:,170; ethylidenedioxy-19-norpregna-1,3,5( 10) ,9 11)-tetraen-20-one (prepared according to the procedure of Example I(af)was converted into 3 hydroxy-14u,Not-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-oxime.

Melting point: 250258 C.

LR. (in KBr): 3425, 3058, 1625, 1604, 1575, 1495, 1400, 1122, 1109, 950,930 cm.-

N.M.R.: (CDCI +DMSO): 6:0.76, 1.27 (doublet), 1.89, 5.20 (quadruplet),6.15, 6.50, 6.60-7.45 (AB-spectrum), 8.4, 9.7 p.p.m.

Molecular ion peak in mass spectrum: 369.

Calculated for C22H2704NZ 369.

EXAMPLE III To a solution of 5 g. of3-methoxy-14a,Not-ethylidenedioxy-19-nor-pregna1,3,5(10),9(11)-tetraen-20-one 20- oxime (prepared according to theprocedure of Example I) in 50 ml. of tetrahydrofuran 8.5 ml. of a 20%solution of butyl lithium in n-hexane and 15 ml. of methyl iodide weresuccessively added. After one hour of refluxing, the conversion beingcomplete, the reaction mixture was dissolved in methyl isobutyl ketone.The solution was washed with water and the solvent evaporated underreduced pressure. The residue was crystallized twice from amethanol/methylene chloride mixture. The yield was 4.06 g. of pure3-methoxy-14zx,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(l1)-tetraen-20-one ZO-O-methyloxime.

Melting point: l60-162 C.

I.R. (in KBr): 3040, 1630, 1605, 1570, 1492, 1400, 1258, 1128, 1110 cmrN.M.R. (in CDCl 5:0.78, 1.28 (doublet), 1. 88, 3.73, 3.83, 5.2(quadruplet), 6.2, 6.5, 6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 397.

Calculated for C H NO 397.

EXAMPLE IV In an analogous way to the procedure described in ExampleIII, 5 g. of 3-methoxy-14a,Not-ethylidenedioxy-19-nor-pregna-1,3,5(l),9(11)-tetraen-20-one 20 oxime were converted with8.5 ml. of butyl lithium solution in nhexane and 10 ml. of benzylbromidein 4.0 g. of pure 3 methoxy-14a,Hot-ethylidenedioxy-19-n0r-pregna-1,3,5l0),9(11)-tetraen-20-one 20-O-benzyl oxime.

Melting point: 115116 C.

I.R. (in KBr): 3090, 3070, 3032, 1630, 1605, 1580, 1569, 1492, 1400,1259, 1128, 1110, 730, 688 cm.-

N.M.R. (in CDCl;,): 6:0.68, 1.25 (doublet), 1.90, 3.68, 5.05, 5.15(quadruplet), 62, 6.55, 6.6 and 7.5 (AB- spectrum) p.p.m.

Molecular ion peak in mass spectrum: 473.

Calculated for C H NO 473.

EXAMPLE V g. of 3rnethoxy-14a,Not-ethylidenedioxy-19-norpregna-1,3,5(l0),9(11)-tetraen-20-one20-oxime were refluxed with 8.5 ml. of n-butyl lithium solution inn-hexane (20%) and 15 ml. of n-propyl iodide in 50 ml. oftetrahydrofuran. The conversion was complete within three hours. Afterthe usual working up 2.67 g. of pure 3- methoxy-l4a,fiat-ethylidenedioxy19 nor-pregna-1,3,5 l0),9(11)-tetraen-20-one ZO-O-n-propyl-oxime wereobtained.

Melting point: 66-68 C.

LR. (in KBr): 3040, 1630, 1608, 1570, 1492, 1400, 1260, 1130, 1110 cmr 8N.M.R. (in CDCl;,): 6:0.81, 0.92 (triplet), 1.29 (doublet), 1.88, 3.71,3.99 (triplet), 5.2 (quadruplet), 6.2, 6.55, 6.6 and 7.5 (AB-spectrum)p.p.m.

Molecular ion peak in mass spectrum: 425. Calculated for C H NO 425.

EXAMPLE VI A solution of 5 g. of3methoxy-l4a,Hot-ethylidenedioxy-l9-nor-pregna1,3,5(lO),9(11)-tetraen-20-one 20- oxime in 50 ml. of anhydroustetrahydrofuran was reacted successively with 8.5 ml. of a n-butyllithium solution in n-hexane (20%) and 15 ml. of isobutyl iodide. Evenafter a refluxing period of 46 hours about ten percent was notconverted. The reaction mixture was dissolved in methyl isobutyl ketone,washed with water and concentrated under reduced pressure. The residuewas dissolved in benzene and chromatographed on a silicagel column withbenzene-3 acetone as eluent.

The desired fractions were collected, the solvent evaporated and theresidue crystallized from methanol. The yield was 3.31 g. of3-methoxy-14a,17a-ethylidenedioxy- 19-nor-pregna-1,3,5(l0),9(l1)tetraen-ZO-one 20-0-(2- methyl) propyl oxime.

Melting point: 97 C.

I.R. (in KBr): 3037, 1629, 1603, 1566, 1491, 1398, 1255, 1124, 1108 cmrN.M.R. (in CDCl 6:0.76, 0.85, 0.94, 1.26 (doublet), 1.86, 3.70, 5.18,6.15, 6.51, 6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 439.

Calculated for C H NO 439.

EXAMPLE VII To a solution of 7.05 g. of3-hydroxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5 10) ,9 1 1)tetraen-20-one in 200 ml. of anhydrous dimethyl formamide 7.2 g. ofsodium hydride and 17.6 g. of 2-dimethylaminoethyl chloridehydrochloride were successively added. For three hours the mixture wasstirred at room temperature. Methyl isobutyl ketone was added and themixture was washed several times with water. The organic solvent wasevaporated under reduced pressure and the residue was dissolved in 560ml. of ethanol. To 280 ml. of this solution were added 10 g. ofhydroxylamine hydrochloride dissolved in 80 ml. of 5% sodium hydroxidesolution. The mixture was refluxed for 20 minutes. Methyl isobutylketone was added and the organic solution was washed several times withwater. The organic solvent was evaporated under reduced pressure, theresidue dissolved in methylene chloride and chromatographed on analumina column with methylene chloride-1% methanol. From the correctfractions 2.0 g. of pure 3-(2-dimethylamino) ethoxy 14a,17aethylidenedioxy 19 nor-pregna- 1,3,5(10),9(11)-tetraen-20-one 20-oximewere obtained.

Melting point: 160-165 C.

LR. (in KBr): 3260, 3060, 3030, 2790, 1630, 1610, 1570, 1500, 1405,1236, 1112, 959 cm.

N.M.R. (in CD01 DMSO-D 6:0.75, 1.25 (doublet), 1.88, 2.54, 3.00(triplet), 4-5 (broad), 4.17 (triplet), 5.20 (quadruplet), 6.20, 6.58,6.67 and 7.53 (AB- spectrum) p.p.m.

EXAMPLE VIII A solution of 5 g. of3-methoxy-l4u,l7a-ethylidenedioxy-19-nor-pregna1,3,5(10),9(11)-tetraen-20-one 20- oxime in 25 ml. of pyridine and 6 ml.of acetic anhydride was kept at room temperature. After one hour ml. ofWater were slowly added and a crystalline precipitate appeared. Aftercooling of the mixture the crystals were filtered otf and dried. Theyield was 5.27 g. of 3-methoxy- 14a,17a-ethylidenedioxy-19-nor-pregna1,3,5 l0 ,9( 1 1 tetraen-ZO-one 20-O-acetyl-oxime. Crystallization froma methanol/methylene chloride mixture yielded 3.44 g. of pure product.

Melting point: 146148 C.

LR. (in KBr): 3028, 2849, 1770, 1630, 1569, 1495, 1402, 1198, 1110 01117N.M.R. (in CDCl 6:0.83, 1.29 (doublet), 2.01, 2.18, 3.73, 5.2(quadruplet), 6.2, 6.55, 6.6 and 7.5 (AB- spectrum) p.p.m.

Molecular ion peak in mass spectrum: 425.

Calculated for C H NO 425.

EXAMPLE IX In an analogous way to the procedure described in ExampleVIII, 5 g. of 3-methoxy-l4a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11) tetraen-20-one 20-oxime were convertedwith pivaloyl chloride into 5.34 g. of pure 3-methoxy l4a,l7otethylidenedioxy 19 nor-pregna- 1,3,5( 10 ,9 1 1 -tetraen-20-one20-O-pivaloyl-oxime.

Melting point: 188-189 C.

IR. (in KBr): 3040, 2838, 1755, 1630, 1609, 1570, 1495, 1260, 1110 cm.

N.M.R. (in CDCl 6:0.86, 1.24, 2.0, 3.73, 5.2 (quadruplet), 6.2, 6.55,6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 467.

Calculated for C23H3I7NO5Z 467.

EXAMPLE X In an analogous way to the procedure described in ExampleVIII, 5 g. of3-methoxy-14u,17a-ethylidenedioxyl9-nor-pregna-1,3,5(10),9(11)tetraen-20-one 20-oxime were converted with 7.5 g. of isonicotinicanhydride into 5.76 g. of pure 3-methoxy-14a,17u-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen 20 one 20-O-isonicotinoyl-oxime.

Melting point: 206209 C.

I.R. (in KBr): 3030, 2830, 1750, 1628, 1600, 1589, 1563, 1552, 1490,1400, 1256, 1240, 1105 cm.-

N.M.R. (in CD61 6:0.90, 1.30 (doublet), 2.15 3.73, 5.2 (quadruplet),6.2, 6.55, 6.6 and 7.5 (AB-spectrum), 7.8, 8.7 p.p.m.

Calculated for C29H32N205I EXAMPLE XI In an analogous way to theprocedure described in Example VIII, 5 g. of3-methoxy-l4a,17a-ethylidenedioxy- 19-nor-pregna-1,3,5(10),9(11)tetraen-20-one 20-oxime were converted with 17.5 g. of benzoic anhydrideinto 5.4 g. of pure3-methoxy-14u,17a-ethylidenedioxy-19-norpregna-1,3,5(10),9(11)tetraen-ZO-one 20 -benzoyloxime.

Melting point: 175-176" C.

IR. (in KBr): 3035, 1750, 1630, 1606, 1581, 1570, 1490, 1402, 1260,1128, 1110, 701 cmr N.M.R. (in CDCl 6:0.91, 1.30 (doublet), 2.13, 3.72,5.23 (quadruplet), 6.2, 6.55, 6.6, 7.47 (multiplet), 8.0 (multiplet)p.p.m.

Molecular ion peak in mass spectrum: 487.

Calculated for C H N0 487.

EXAMPLE XII To a solution of 5 g. of3-methox'y-14u,l7a-ethylidenedioxy-19-nor-pregna 1,3,5 (),9(11) tetraen20 one 20-oxime in pyridine 5 g. of adarnantane carbonyl chloride wereadded. After one hour, the conversion being complete, water, andmethylene chloride were added. The mixture was shaken, the organic layerseparated and Washed with N sodium hydroxide solution and with wateruntil neutral. After evaporating the solvent under reduced pressure theresidue was crystallized from boiling methanol. 6.3 g. of pure3-methoxy-14a,17a-ethylidenedioxy- 19-nor-pregna-1,3,5 10) ,9 (1 1-tetraen-20-one 20-O-adamantanecarbonyl-oxime were obtained.

Melting point: 232236 C. (destr.).

I.R. (in KBr): 3038, 1758, 1630, 1605, 1568, 1492, 1400, 1103 cm.-

10 N.M.R. (in CDCI 6:0.85, 1.28, 1.75, 2.0, 3.73, 5.2 (quadruplet), 6.2,6.55, 6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 545. Calculated for C H NO 545.

EXAMPLE XIII 10 g. of 3-methoxy -14a,17otethylidenedioxy-19-norpregna-1,3,5(10),9(11)-tetraen-20-one 20-oxime and20 ml. of myristoylchloride were dissolved in 50 ml. of pyridine. After30 minutes of stirring at room temperature, the conversion beingcomplete, water was added. The fatty precipitate was collected (18.2g.). To remove the excess m'yristic acid the crystals were stirred with75 ml. of heptane. After filtration, evaporation of the solvent andrecrystallization of the residue in ml. of Warm heptane 6.38 g. of pure3-methoxy-14a,17u-ethy1idenedioxy-19-nor-pregna 1,3,510),9(-11) tetraen-20 one ZO-O-myristoyl-oxime were obtained.

Melting point: 82-84.5 C.

IR. (in KBr): 3060, 3028, 1780, 1735, 1625, 1605, 1568, 1492, 1403,1225, 1103 cm."

N.M.R. (in CD01 6:0.83, 0.88 (triplet), 1.26, 1.3 (doublet), 2.0, 3.73,5.2 (quadruplet), 6.2, 6.55, 7.5 and 61.6 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 593.

Calculated for C H NO 593.

EXAMPLE XIV A solution of 18 ml. of chlorosulfonic acid in 50 ml. ofanhydrous methylenechloride was dropwise added to 100 ml. of anhydrouspyridine. The mixture was fastly stirred and kept at a temperature of-20-0 C. with an acetone/Dry Ice mixture. To the thick slurry a solutionof 4.2 g. of3-hydroxy-14a,17a-ethylidenedioxy-19-norpregna-'1,3,5*(10),9(11)tetraen-ZO-one 20-oxime in 50 ml. of anhydrous pyridine was added. Themixture was heated until a clear solution was obtained. The reactionmixture was diluted with water and the methylenechloride layerseparated. The water layer was extracted four times with 250 ml. ofether to remove the pyridine and was next acidified with 6 N sulfuricacid to pH=1. After adding acetone and shaking, two layers were formed.Within two days crystals precipitated from the separated water layer.After filtration and drying 1 g. of product was obtained. This wasrecrystallized from acetone and chromatographic pure14a,17m-ethylidenedioxy-20-hydrogen sulfate imin-o19-n0r-pregna-1,3,5(10),'9(1l)-tetraen-3-yl 3-hydrogen sulphate wasobtained.

Melting point of the sodium salt: C. (decomp.).

I.R. (in KBr): 32504050, 2700, 1630, 1603, 1563, 1485, 1400, -1270,-1210, 1132, 1103 cmr' N.M.R. (in sodium bicarbonate solution): 6:7.6,1.27 (doublet), 2.00, 5.32 (quadruplet), 6.38, 7.00, 7.05, 7.70(AB-spectrum) p.p.m.

EXAMPLE XV 10 g. of 3-methoxy l4oz,l7otethylidenedioxy-19-norpregna-1,3,5(10),9(11)-tetraen-20-one wererefluxed for three hours in 100 ml. of ethanol with 40 ml. oftriethylamine and 10 m1. of hydrazine hydrate. The reaction product wasprecipitated by the addition of water and after cooling 7.94 g. of thehydrazone were obtained. These were crystallized from a methanol/methylene chloride mixture, yielding 6.20 g. of pure3-methoxy-14a,17aethylidenedioxy 19 nor-pregna-1,3,5(10),9(*11)-tetraen- 20-0ne 20-hydrazone.

Melting point: 146148 C.

LR. (in KBr): 3396, 3040, 1630, 1604, 1568, 1492, 1400, 1270, 1128,1'110 cmf N.M.R. (in CD01 5:0.73, 1.29 (doublet), 1.76, 3.72, -5.0(broad), 5.2 (quadruplet), 6.2, 6.55, 6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 382.

Calculated for C H N O 3'82.

EXAMPLE XVI g. of3-methoxy-14a,17a-ethylidenedioxy-l9-norpregna-l,3,5(),9(1=1)-tetraen-20-onewere refluxed for 3.5 hours in 35 ml. of ethanol (96%) and ml. of methylhydrazine. After cooling the precipitate crystals were collected anddried (5.10 g.). After crystallizing from a methanol/methylene chloridemixture 3.9 g. of pure 3 methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5 10),9( 1 1 -tetraen--one ZO-N-methyl hydrazone were obtained.

Melting point: 174-189 C.

I.R. (in KBr): 3303, 3035, 2800, 1630, 1603, 1567, 1492, 1400, 1255,1125, 1103 cm.-

N.M.R. (in CDCI 5:0.74, 1.28, 1.72, 2.90, 3.7 1, -42 (broad), 5.2(quadruplet), 6.2, 6.55, 6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 396.

Calculated for C24H32N203:

EXAMPLE XVII In an analogous way to the procedure described in ExampleXVI, 4.5 g. of 3-hydroxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(l0),9(11)-tetraen-20-one were converted to 4.6 g. ofpure 3-hydroxy-14a,l7a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-N- methyl hydrazone.

Melting point: 220-225" C.

LR. (in KBr): 3350, 3243, 1630, 1605, 1572, 1444, 1402, 1110 cm.-

N.M.R. (in CDCl +DMSO): 6:0.73, 1.25, 1.72, 2.88, 4.0 (broad), 5.2(quadruplet), 6.13, 6.5, 6.55 and 7.45 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 382.

Calculated for C H O N 382.

EXAMPLE XVIII To a solution of 15 g. of3-hydroxy-14a,17a-ethylidenedioxyl9-norpregna-l,3,5(10),9(11)-tetraen-20-one in 300 ml. oftetrahydrofuran were successively added 13 ml. of a butyl lithiumsolution in n-hexane (20%) and 30 ml. of isopropyl iodide. The mixturewas refluxed on the steam bath for three days. After the usual workingupthe reaction product was chromatographed on a silicagel column withbenzene. The desired fractions were collected, the solvents evaporatedand the residue crystallized from methanol.

The yield Was 5.25 g. of 3-isopropoxy-14u,17aethylidenedioxyl9-nor-pregna-1,3,5( 10) ,9, 1 1 )-tetraen- 20-one. The N.M.R. spectrumwas in agreement with the expectation.

Melting point: 79-82 C.

A solution of 3 g. of the isopropyl-ether in 20 ml. of ethanol wasrefluxed with 15 ml. of methyl hydrazine during 7 hours. After coolingwater was added and from this mixture 2.95 g. of chromatographic pure3-isopropoxy 140:,17a ethylidenedioxy-19-nor-pregna-l,3,5-(10),9(l1)-tetraen-20-one 20-N-methyl hydrazone were obtained.

Melting point: 120-l31 C.

I.R. (in KBr): 3290, 3030, 1630, 1608, 1565, 1492, 1407, 1255, 1125,1110 cmr' N.M.R. (in CDCI 6:0.76, 1.28 (doublet), 1.72, 2.92, 4.0-5.0(broad), 4.46 (septet), 5.21 (quadruplet), 6.21, 6.5, 6.6 and 7.5(AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 424.

EXAMPLE XIX 5 g. of3-methoxy-14a,17a-ethylidenedioxy-19-norpregna-l,3,5(10),9(l1)-tetraen-20-onewere refluxed for one hour in a mixture of 35 ml. of ethanol (96%), 35ml. of triethylamine and 10 g. of ethyl hydrazine oxalate. Water wasadded and the precipitated crystals were filtered off and recrystallizedfrom a methanol/chloride mixture. 4.2 g. of pure3-methoxy-14u,17a-ethylidenedioxy 19 norpregna-1,3,5(10),9(11)-tetraen20one- 20-N-ethyl hydrazone were obtained.

Melting point: 168-176 C.

I.R. (in KBr): 3280, 3032, 1630, 1605, 1568, 1492, 1409, 1255, 1130,1110 cmf N.M.R. (in CDCI 6:0.75, 1.12 (triplet), 1.28 (doublet), 1.72,3.2 (quadruplet), 3.7, 4.25, 5.18 (quadruplet), 6.2, 6.55, 6.6 and 7.5(AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 410.

Calculated for C H N O 410.

EXAMPLE XX In an analogous way to procedure described in Example XIX, 5g. of3-methoxy-14a,l7a-ethylidenedioxy-19-norpregna-1,3,5(10),9(11)-tetraen-20-onewere converted with 10 g. of propyl hydrazine oxalate to 4.9 g. of pure3-methoxy-14u,17a ethylidenedioxy 19 nor pregna-1,3,5(10),9(11)-tetraen-20-one 20-N-pr0pyl hydrazone.

Melting point: 169-176 C.

I.R. (in KBr): 3300, 3270, 3032, 1630, 1602, 1565, 1490, 1403, 1125,1110 cm.-

N.M.R. (in CDCl:.;): 6:0.73, 0.90 (triplet), 1.28 (doublet), 1.72, 3.1(triplet), 3.7, 4.45, 5.15 (quadruplet), 6.2, 6.55, 6.6 and 7.5(AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 424.

Calculated for C25H36N203:

EXAMPLE XXI A solution of 5 g. of 3-rnethoxy-14a,l7a-ethylidenedioxy 19nor pregna-1,3,5(10),9(11)-tetraen-20-one in ml. of anhydrous benzenewas refluxed with 100 ml. of anhydrous asymm.-dimethylhydrazine for 72hours. The benzene and the dimethyl hydrazine were removed byevaporation under reduced pressure and the residue was chromatographedon a silicagel-column with the eluent toluene-1% acetone. 2.2 g. ofstarting material were recovered and 0.53 g. of3-methoxy-14a,17x-ethylidenedioxy 19 nor pregna-1,3,5(10),9(11)-tetraen-20-one 20-N,N-dimethyl hydrazone were obtained.

Melting point: 133-135 C.

LR. (in KBr): 3083, 3035, 2770, 1630, 1605, 1570, 1496, 1404, 1259,1128, 1111, 1040, 804 CHI-'1.

N.M.R. (in CDCl,): 6:0.77, 1.28 (doublet), 2.00, 2.44, 3.75, 5.20(quadruplet), 6.20, 6.5, 6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 410. I

Calculated for C H O N 410.

EXAMPLE XXII A solution of 5 g. of3-methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(l1)-tetraen-20one 20- hydrazone in 50 ml. of pyridine was stirred at room temperaturewith 2.5 ml. of acetic anhydride, After one hour water was added andfrom the cooled mixture 3.70 g. crystalline product could be isolated.After recrystallization from a methanol/methylene chloride mixture 3.60g. of pure3-methoxy-14a,17a-ethylidenedioxy-19-norpregna-l,3,5(10),9(l1)--tetraen-20-one20-n-acetyl hydrazone were obtained.

Melting point: 152-l55 C.

IR. (in KBr): 3185, 1680, 1630, 1608, 1568, 1498, 1405, 1238, 1125, 1110cmr' N.M.R. (in CDC1 6:0.77, 1.29 (doublet), 1.90, 2.24, 3.73, 5.2(quadruplet), 6.2, 6.55, 6.6 and 7.5 (AB- spectmm), 9.05 p.p.m.

Molecular ion peak in mass spectrum: 424.

Calculated for C H N O 424.

EXAMPLE XXIII In an analogous way to the procedure described in ExampleXXII, 5 g. of 3-methoxy-14a,17a-ethylidenedioxy- 19-nor-pregna-1,3,5l0),9(11)-tetraen-20-one 20 hydrazone were converted with 2.5 ml. ofpropionic anhydride into 4.20 g. of pure3-methoxy-14a,17a-ethylidenedioxy- 1319-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-N-propionyl hydrazone.

Melting point: 203-205 C.

IR. (in KBr): 3200, 3030, 1685, 1630, 1610, 1565, 1500, 1400, 1230,1123, 1110 cmr N.M.R. (in CDCl 6:0.75, 1.17 (triplet), 1.3 (doublet),1.92, 2.65 (quadruplet), 3.7, 5.2 (quadruplet), 6.2, 6.55, 6.6 and 7.5(AB-spectrum), 9.3 p.p.m.

Molecular ion peak in mass spectrum: 438.

Calculated for C H N O 438.

EXAMPLE XXIV In an analogous way to the procedure described in ExampleXXII, g. of3-methoxy-14u,17ot-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20one 20- hydrazone were converted with 4 ml. of pivalic anhydride into5.3 g. of 3-methoxy-14a,17a-ethylidenedioxy-19-norpregna-1,3,5 ,9 1 1-tetraen-20-one 20-N-pivaloyl hydrazone.

Melting point: 108111 C.

I.R. (in KBr): 3435, 3300, 3060, 3027, 1660, 1605, 1568, 1510, 1496,1403, 1230, 1128, 1110cmf N.M.R. (in CDCl 6:0.77, 1.3, 1.90, 3.4, 3.72,5.2 (quadruplet), 6.2, 6.55, 6.6 and 7.5 (AB-spectrum), 8.40 p.p.m.

Molecular ion peak in mass spectrum: 466.

Calculated for C H N O 466.

EXAMPLE XXV A solution of 5 g. of3-methoxy-14u,17a-ethy1idenedioxy-l9-nor-pregna-1,3,5(10),9(11)-tetraen-20one 20- hydrazone in 50 ml. of pyridine was reacted for 2 hours with10.5 of isonicotinic anhydride. The desired product was separated bycolumn-chromatography (silicagel, with benzene-10% acetone as eluent)from some less polar materials. After crystallization from amethanol/water mixture 5.05 g. of pure 3-methoxy-14u,17a-ethylidenedioxy19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20- N-isonicotinoylhydrazone were obtained.

Melting point: 127-132 C.

I.R. (in KBr): 3440, 3030, 2838, 1660, 1603, 1550, 1492, 1403, 1230,1123, 1103 cmr N.M.R. (CDCl -l-DMSO): 6:0.75, 1.27 (doublet), 2.03,3.70, 5.2, 6.2, 6.55, 6.6, 7.5 (multiplet), 8.6 (doublet), 10.1 p.p.m.

Molecular ion peak in mass spectrum: 487.

Calculated for C H N I 487.

EXAMPLE XXVI In an analogous way to the procedure described in ExampleXXII, 5 g. of3-methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(l1)-tetraen-20-one20-hydrazone were converted with 8 g. adamantane carbonyl chloride, into6.5 g. of pure 3-methoxy-14u,17a-ethylidenedioxy-l9-nor-pregna-1,3,5 10),9 1 1 )-tetraen-20 one 20-N,N-diadarnantane carbonyl hydrazone.

Melting point: 203-206 C.

LR. (in KBr): 3025, 1750, 1645, 1603, 1565, 1491, 1399, 1125, 1110 cm.-

N.M.R. (in CDCl 6:0.80, 1.27 (doublet), 1.70, 1.91, 1.95, 3.72, 5.2(quadruplet), 6.2, 6.55, 6.6 and 7.5 (AB-spectrum) p.p.m.

EXAMPLE XXVII In an analogous way to the procedure described in ExampleXXII, 5 g. of 3-methoxy-l4u,17a-ethylidenedioxy-19-nor-pregna-1,3,5 10),9 11)-tetraen-20-one 20-hydrazone were converted with 6 ml. of pivalylchloride to 4.45 g. of pure 3-methoxy-14a,17ot-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(1 1)-tetraen-20-one 20-N,N-dipivalyl hydrazone.

Melting point: 114-116 C.

LR. (in KBr): 1751, 1649, 1607, 1570, 1495, 1223, 1120 cm.-

14 N.M.R. (in CDCl 6:0.78, 1.2, 1.91, 3.7, 5.17 (quadruplet), 6.2, 6.55,6.6 and 7.5 (AB-spectrum) p.p.m.

Molecular in peak in mass spectrum: 550. Calculated for C33H45N2053EXAMPLE XXVIII 3 g. of3-hydroxy-14a,17ot-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one20-N-methyl hydrazone were dissolved in 15 ml. of pyridine and reactedfor 30 minutes at room temperature with 3.75 ml. of acetic anhydride. 10ml. of methanol were added and the mixture was shaken with methylisobutyl ketone. It was washed several times with water and the organiclayer was concentrated by evaporation under reduced pressure. Theresidue was crystallized from heptane. 3.15 g. of 1404,170;ethylidenedioxy-20-(N,N-methyl, acetylamino) imino-19-nor-pregna-1,3,5(10),9(11)-tetraen-3 yl 3-acetate were obtained.

Melting point: 173 C.

I.R. (in KBr): 3035, 1760, 1660, 1490, 1403, 1200, 1128, 1112 cmf N.M.R.(in CDCl 6: 0.80, 1.29 (doublet), 1.95, 2.02, 2.23, 3.10, 5.20(quadruplet), 6.30, 6.75, 6.82, and 7.60 (AB-spectrum) p.p.m.

Molecular ion peak in mass spectrum: 466.

Calculated for C H O N 466.

EXAMPLE XXIX To a cooled solution of 2.5 g. of3-hydroxy-14ot,17aethylidenedioxy-19-nor-pregna 1,3,5(10),9(11) tetraen-20-one 20-N-methylhydrazone in 20 ml. of pyridine 3 ml. of 2-thiophenecarbonyl chloride were dropwise added. After 15 minutes water was added,the mixture was shaken with methyl isobutyl ketone and several timeswashed with water. After concentration of the organic layer byevaporation under reduced pressure the residue was purified bychromatography on a silicagel column. Eluent was benzene-2% acetone. Theyield was after crystallization from methanol 3.1 g. of pure14a,17a-ethylidenedioxy-20- (N,N-methyl 2-thiophene carbonyl-amino)imino-l9-norpregna-1,3,5(10),9(11)-tetraen-3-yl 3-thiophene carboxylate.

Melting point: 206209 C.

I.R. (in KBr): 3113, 3093, 3030, 1727, 1630, 1522,1488,1258,1208,1111,1058 728 cm."

N.M.R. (in CDCl DMSO-d pyr d 5:0.85, 1.37 (doublet), 2.05, 3.34, 5.31(quadruplet), 6.37 (broad), 6.9-8.0 (multiplet) p.p.m.

Molecular ion peak in mass spectrum: 602.

Calculated for C33H34N105S2I EXAMPLE XXX To a solution of 2.5 g. of3-hydroxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11) tetraen20-one ZO-N-methyl hydrazone in 20 ml. of pyridine 7 g. of adamantanecarbonyl chloride were added. The mixture was stirred for 16 hours atroom temperature. Next, water was added and the mixture was shaken withmethyl isobutyl ketone. It was washed with water several times and theorganic layer was concentrated by evaporation under reduced pressure.The residue was ehromatographed on a silicagel column with the eluentbenzene-2% acetone. From the correct fractions 2.38 g. of pure14a,17a-eth'- ylidenedioxy 20 (N,N-methyl, adamantane carbonylamino)imino-19-nor-pregna 1,3,5 10),9( 1 1) tetraen-3- yl 3-adamantanecarboxylate were obtained (after crystallization from amethanol/methylene chloride mixture).

Melting point: 194-198 C.

IR. (in KBr): 3030, 1756, 1650, 1438, 1405, 1205, 1113, 1103, 1053 cmrN.M.R. (in CDCI 6:0.81, 1.32 (doublet), 197, 1.83 and 2.05, 3.07, 5.23(quadruplet), 6.30 (broad), 6.7, 6.6 and 7.7 (AB-spectrum) p.p.m.

1 5 EXAMPLE XXXI To a solution of 42 g. of semicarbazide hydrochloridein 105 ml. of water 105 ml. of sodium hydroxide solution (10%) wereadded. The mixture was filtrated and then added to a hot solution of10.5 g. of 3-methoxy-14a, 17a-ethylidenedioxy 19nor-pregna-l,3,5(l),9(11)- tetraen-ZO-one in 735 ml. of ethanol (96%After half a minute a turbidity appeared. The precipitate was filtered,dried and recrystallized from a mixture of dimethyl formamide and methylisobutyl ketone. 5.5 g. of pure 3-methoxyl4a,17u-ethylidenedioxy 19nor-pregna-1,3,5(10), 9(11)-tetraen-20-one 20-semicarbazone wereobtained.

Melting point: 263266 C.

I.R. (in KBr): 3480, 3190, 3030, 1700, 1630, 1604, 1565, 1493, 1255,1125, 1110 cmr N.M.R. (in CD013, DMSO-d pyr-d 6:0.72, 1.22 (doublet),1.87, 3.72, 5.2 (quadruplet), 6.25, 6.62, 6.70 and 1.51 (AB-spectrum)p.p.m.

Molecular ion peak in mass spectrum: 425.

Calculated for C H O N 425.

EXAMPLE XXXII A solution of g. of methoxy-14a,17u-ethylidenedioxy-19-nor-pregna-1,3,5(l0),9(11) tetraen 20-one in 50 ml. ofdimethylformamide and 50 ml. of methanol was refluxed for 18 hours with3 g. of Girards T reagent.

The reaction mixture was cooled and dissolved in methyl isobutyl ketone.The solvent was evaporated under pressure. The residue was dissolved inmethylene chloride and chromatographed on a silicagel column with theeluent methylene chloride-20% methanol.

After evaporating of the solvent of the correct fractions the residuewas crystallized from methanol and 4.35 g. of the pure Girards Tderivative of 3-methoxy-14a,l7a-ethylidenedioxy-l9-nor-pregna1,3,5(10),9(11) tetraen- 20-one were obtained.

Melting point: 253-255 C. (destr.).

I.R. (in KBr): 3420, 3150, 1699, 1630, 1609, 1568, 1535, 1498, 1405,1230, 1110 cm.-

N.M.R. (in CDCl +DMSO): 5:0.80, 1.29 (doublet), 2.20, 3.47, 3.77, 4.85(doublet), 5.21 (quadruplet), 6.20 (broad), 6.58 6.68 and 7.55(AB-spectrum) p.p.m.

What we claim and desire to secure by Letters Patent 1.ZO-iminopregnatetraene derivative of the formula:

wherein R represents a hydrogen atom, a lower alkyl group having lessthan 4 carbon atoms and which may be substituted by a dimethylaminogroup, or an acyl residue derived from an organic carboxylic acid havingless than 12 carbon atoms or an acyl residue derived from sulfuric acid;R represents a hydroxyl group or 0R wherein R represents a lower alkylgroup having less than 5 carbon atoms, a benzyl group or an acyl residuederived from an organic carboxylic acid having less than 15 carbon atomsor an acyl residue from sulfuric acid, or R represents NH the group-NI-ICONH the group NHCOCH N+ (CH 3 CL- or a group 16 wherein Rrepresents a hydrogen atom, a methyl group or an acyl residue derivedfrom an organic carboxylic acid, having less than 12 carbon atoms and Rrepresents an alkyl group having less than 4 carbon atoms or an acylresidue derived from an organic carboxylic acid having less than 12carbon atoms.

2. 20-iminopregnatetraene derivative according to claim 1, wherein Rrepresents a methyl group and R represents a hydroxyl group or a group Rwherein R represents a lower alkyl group having less than 5 carbonatoms, a benzyl group or an acyl residue derived from an organiccarboxylic acid having less than 15 carbon atoms.

3. 20-irniopregnatetraene derivative according to claim 1, wherein Rrepresents a hydrogen atom or the B-dimethylaminoethyl group and Rrepresents a hydroxyl.

4. ZO-iminopregnatetraene derivative according to claim 1, wherein R andR represent an acyl residue derived from an sulfuric acid.

5. 20-iminopregnatetraene derivative according to claim 1, wherein Rrepresents a methyl group and R represents -NH or -NHCONH the group or agroup -NR R wherein R and R are as defined in claim 1.

6. 20-iminopregnatetraene derivative according to claim 1, wherein Rrepresents a hydrogen atom or an alkyl group having less than 4 carbonatoms, R represents a hydrogen atom and R represents the methyl group.

7. 20-iminopregnatetraene derivative according to claim 1, wherein R andR are the same and represent an acyl residue derived from an organiccarboxylic acid having less than 12 carbon atoms and R represents amethyl group.

8. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14u,l7a-ethylidenedioxy-l9 norpregna-1,3,S 10),9(11)-tetraene-20-one 20 oxime.

9. 20-iminopregnatetraene derivative according to claim 1, which is3-hydroxy-l4a,17a-ethylidenedioxy 19 norpregna-1,3 ,5 10 ,9( 1 1)-tetraen-20-one 20-0xime.

10. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17u-ethylidenedioxy-19-nor-pregna-1,3,5(l0),9(1l)tetraen-20-one 20-0 methyloxime.

11. 20-imin0pregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-19- nor-pregna-1,3,5(10),(11)-tetraen-20-one 20-0 benzyloxime.

12. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-l,3,5(10),9(11)-tetraen-20-0ne ZO-O-n-propyloxime.

13. ZO-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14u,17a-ethylidenedioxy-19- nor-pregna-1,3,5(10),9(11)-tetraen20 one 20 O (2- methyl propyl-oxime.

14. 20-iminopregnatetraene derivative according to claim 1, which is3-(2-dimethylamino)ethoxy14a,17methylidenedioxy-l9-nor-pregna-1,3,5(10),9(11) tetraen- 20-one20-oxime.

15. ZO-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(1l)-tetraen-20-one 20-0 acetyloxime.

16. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-19- nor-pregna-1,3,5 l0) ,9 l1)-tetraen-20-one 20-O-pivaloyloxime.

17. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14'a,17u-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-O-isonicotinoyl-oxime.

18. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-19- 17 nor-pregna-1,3,5(10),9(11)-tetraen-20-one ZO-O-benzoyloxime.

19. 20-iminopregnatetraene derivative according to claim 1, which is3-rnethoxy-14a,17a-ethylidenedioxy19-nor-pregna-1,3,5(10),9(1l)-tetraen-20 one 20 O-adamtanecarbonyl-oxime.

20. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-l4tx,l7a-ethylidenedioxy-l9- nor-pregna-l,3,5(10),9(1l)-tet1'aen-20-one 20-0 myristoyl-oxime.

21. 20-iminopregnatetraene derivative according to claim 1, which is141x,l7a-ethylidenedioxy-29-hydrogen sulphate imino-l9-nor-pregna-l,3,5(10) ,9 (1 1 -tetraen-3- yl 3-hydrogen sulphate.

22. ZO-iminopregnatetraene derivative according to claim 1, which is3-methoxy-l4a,17a-ethylidenedioxyl9- nor-pregna-1,3,5(10),9(1l)-tetraen-20-one ZO-hydrazone.

23. ZO-iminopregnatetraene derivative according to claim 1, which isS-methoxy-14w,17a-ethylidenedioxy-19- nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-N-methyl hydrazone.

24. ZO-iminopregnatetraene derivative according to claim 1, which is3-hydroxy-14a,l7a-ethylidenedioxy-l9- nor-pregna- 1,3,5 1 ),9(11)-tetraen-20-one 20-N-methyl hydrazone.

25. ZO-iminopregnatetraene derivative according to claim 1, which is3-isopropoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),'9(11)-tetraen 20 one 20 N- methyl hydrazone.

26. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-l4ot,l7a-ethylidenedioxy-19-nor-pregna-1,3,5(),9(11)-tetraen-20 one ZO-N-ethyl hydrazone.

27. 20 irninopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-l9-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-N propyl hydrazone.

28. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-N,N dimethyl hydrazone.

29. ZO-iminopregnatetraene derivative according to claim 1, which isS-methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(19),9(1l)-tetraen-20-one ZO-N acetyl hydrazone.

30. ZO-irninopregnatetraene derivative according to claim 1, which is3-methoxy-14u,17ot-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20-N propionyl hydrazone.

31. ZO-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14u,17u-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(11)-tetraen-20-one ZO-N-pivaloyl hydrazone.

32. ZO-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,l7a-ethylidenedioxy-l9- nor-pregna-1,3,5( 10 ,9( l 1-tetraen-20-one 20-N-isonicotinoyl hydrazone.

33. ZO-iminopregnatetraene derivative according to claim 1, which isB-methoxy-l4a,l7u-ethylidenedioxy-l9-nor-pregna-1,3,5(10),9(11)-tetraen-20-one 20 N,N di adamantane carbonylhydrazone.

34. ZO-iminopregnatetraene derivative according to claim 1, which is3-methoXy-14a,l7a-ethylidenedioxy-l9-nor-pregna-1,3,5(l0),9(l1)-tetraene-20-one 20-N,N dipivaloyl hydrazone.

35. ZO-iminopregnatetraene derivative according to claim 1, which is14u,l7a-ethylidenedioxy 20 (N,N- methyl, acetylamino) imino-l9-norpregna l,3,5(10), 9 l l )-tetraen-3-yl S-acetate.

36. 20-iminopregnatetraene derivative according to claim 1, which is14a,17a-ethylidenedioxy 20 (N,N- methyl,2-thiophene carbonyl-amino)imino-19-nor-pregna- 1,3,5 l0),9(11)-tetraen-3-yl-3 thiophenecarboxylate.

37. ZO-iminopregnatetraene derivative according to claim 1, which isl4a,l7a-ethylidenedioxy 20-(N,N- methyl, adamantane carbonyl amino)imino 19 norpregna-1,3,5(10),9(11)-tetraen-3-yl 3 adamantanecarboxylate.

38. 20-iminopregnatetraene derivative according to claim 1, which is3-methoxy-l4a,17u-ethyldienedioxy-19 nor-pregna-l,3,5 (l0),9(1l)-tetraen-20-one ZO-Semicarbazone.

39. ZO-iminopregnatetraene derivative according to claim 1, which is3-methoxy-14a,17a-ethylidenedioxy-19-nor-pregna-1,3,5(10),9(l1)-tetraen-20-one in the form of its Girards Tderivative.

40. Pharmaceutical composition which comprises as the active ingredient,at least one ZO-iminopregnatetraene derivative as defined in claim 1 ina pharmacologically effective amount in association with a non-toxicpharmaceutically acceptable carrier.

References Cited UNITED STATES PATENTS 6/1971 Marx et al 260239.552/1971 Marx et al. 260-239.55

OTHER REFERENCES ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R.

